jeremiah murphy, md mercy urology clinic testosterone may be a crucial factor in chronic disease...

Jeremiah Murphy, MD Mercy Urology Clinic

October 21, 2017

● Describe an appropriate strategy for the evaluation and diagnosis of male hypogonadism ○ Endocrine Society Clinical Practice Guideline-2010

● Review the potential benefits of testosterone replacement therapy

● Discuss the risks associated with testosterone replacement therapy

● Discuss age-related hypogonadism ● Controversial topics in testosterone replacement therapy

○ Cardiovascular risks, PSA, prostate cancer, LUTS

A Bit of History:

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Arnold Berthold

1849

Charles Brown-Sequard

“Elixer of life”

Testicular Extract

1889

Testosterone Synthesized Butenandt and Ruzicka (independant) Nobel Prize 1939

1935

The Male Climacteric

Heller & Myers

Symptom complex

1944

Big Business “Low-T” Topical preparations

1990s +

“ Low-T”

● Significant increase in the sale of Testosterone products

○ 18 million dollars in 1988

○ 1.6 billion dollars in 2011

○ 5.3 million Rx in 2011

● Direct-to-consumer advertising

● Low-T or Men’s Health Clinics

● Improved formulations

“Low-T”

● Institute of Medicine NASC 2002

○ No beneficial effect is well established

● JAMA 2013

○ 3x increase in testosterone Rx

○ 25 % never had diagnostic test for low testosterone

● FDA 2015

Men’s Health Issues 2017:

● Erectile Dysfunction

● Vitality

● Physical

● PSA and Prostate Disease

● Bone and Joint Health

● Cardiovascular Disease

● Dietary Health/Health Maintenance

Testosterone:

● Testosterone is important

● Direct and indirect effects on every organ system in the body

● Low testosterone may be a crucial factor in chronic disease states

● Shifting demographics-aging population

● Estimated over 5 million men are affected

● Benefits of treatment can be significant

Testosterone:

Testosterone:

● Primary Circulating Androgen

○ Libido, Anabolic effects, Hematologic effects, Bone Metabolism, Mood, Insulin, CV

effects

● Adrenal Cortex 5%

● Androgen Receptor (AR) present in most tissues

● AR + Ligand conformal change- DNA-binding transcription factor that regulates gene expression

Testosterone Effects:

● Muscle Mass

● Bone Formation

● Sexual Function

● Via DHT ○ Facial and Body Hair

○ Scalp Hair Loss

○ Prostate Growth

○ Acne

● Via Estradiol ○ Bone Health

○ Cognitive and Verbal Function

Indispensable:

History and Physical Exam Signs and Symptoms*

Morning Total Testosterone

*Only screen men if signs or symptoms are present. Universal screening is not recommended. *Don’t test during an acute illness or hospitalizatoin (suppressed rhythm/IL-1) *Symptoms are nonspecific

Symptoms:

● Specific ○ Decreased sexual desire/Libido ○ Decreased spontaneous erections ○ Gynecomastia ○ Loss of body hair, reduced shaving ○ Loss of Height ○ Low BMD ○ Low trauma fracture

● Less specific

○ Decreased energy ○ Decreased motivation ○ Feeling sad ○ Decreased concentration or memory ○ Sleep disturbance ○ Mild anemia ○ Decreased muscle mass ○ Increased body fat ○ Diminished work/physical performance

Summary

● Muscle vs Fat ● Sexual Function

● Physical function

● Mood/Concentration

● Sleep

● Energy/Vitality

● Bone density

History and Physical Exam


● Check Total testosterone in the am 7-9 am

● Testosterone levels peak at around 8 am

Rhythm is blunted by illness or sleep disturbance Check only in baseline state

History and Physical Exam


Normal <300 ng/dL Follow up

Low Testosterone

Low Testosterone (<300 ng/dL)

● Exclude reversible illness, drugs, nutritional deficiency

● Repeat AM free and total testosterone

● LH and FSH

● 30 % of men with initially low testosterone will have a normal

level on repeat testing

● Total Testosterone significantly by SHBG ● Glycoprotein that binds androgen and estrogen

○ Decreased SHBG

■ Hypothyroidism ■ Obesity ■ Diabetes ■ Androgens

○ Increased ■ Age related increase ■ Hyperthyroidism ■ Malnutrition ■ Liver disease


● Low total testosterone but normal free-T

○ Symptoms unlikely related to low testosterone

● Normal Testosterone, LH + FSH

Follow up


Low T, low or normal LH + FSH

(Secondary Hypogonadism) ● Prolactin ● Iron ● Pituitary hormones ● MRI selected cases

Low T, High LH + FSH

(Primary Hypogonadism) ● Klinefelter syndrome ● Receptor gene mutations ● Cryptorchidism ● Disorders of androgen synthesis

Testosterone and Replacement Considerations:

● Anabolic Effects ○ Testosterone increases lean body mass ○ Decreases fat ○ Effects stem cell differentiation ○ Increases protein synthesis ○ Inhibits protein degradation

● Hematologic Effects

○ Increases red cell mass ○ Increases HgB concentration ○ Erythrocytosis more pronounced with IM injections ○ Less with transdermal formulations ○ Must follow HgB levels


● Bone Metabolism Effects ○ Multiple pathways ○ Testosterone Estradiol inhibits bone resorption ○ Testosterone replacement increases BMD ○ Does T-replacement decrease fracture risk ?

● Mood and Cognition ○ T-replacement improves the positive/reduces the negative ○ Effects on depression unclear. Ongoing research ○ Improves visual cognition ○ Improves verbal memory ○ Improves verbal fluency


● Chronic disease states ○ Centrally mediated effect

■ Stress ■ Malnutrition ■ Opiate use ■ Infection

● Aging Male ○ Growing population >65 years old ○ Desire to maintain physical and sexual function ○ Greater percentage of older men have lower testosterone

Testosterone in the Aging Male:

● European Male Aging Study J. Clin Endocrino Metab 2008 93:2737

● Massachusetts Aging Study J. Clin Endocrinology Metab 2007; 92:549

● New Mexico Aging Process Study Metabolism 1997; 46:410

The Aging Male

● Decease in both total and free T

● 100 ng/dL from 20 to 80

● 0.4%/year

● Loss of diurnal variation

● Increased SHBG

● Mild elevation in FSH + LH

● Mixed primary and secondary

hypogonadism

The Testosterone Trials (NEJM 2016; 374:611):

● Multicenter seven placebo-controlled trials ● Looked at one year efficacy of testosterone in older men with established low-T ● Looked at effects on:

○ Sexual Function ○ Physical Function ○ Vitality ○ Cognitive Function ○ Anemia ○ Bone Density ○ Cardiovascular Risk Factors

The Testosterone Trial Results:

● Sexual Function ○ Moderate improvement in activity and sexual desire

● Physical Function

○ No significant difference between treatment group and placebo

● Vitality ○ No significant difference but men on testosterone did report a better mood

● Cognitive Function

○ No change over baseline (with exception in some improvement in executive function when subject groups combined)

The Testosterone Trial Results:

● Anemia ○ Significant improvement in hemoglobin of 1 g/dL or more in treatment group

● Bone density ○ Testosterone significantly increased BMD (lumbar, hip and peripheral)

● Cardiovascular risks

○ Increase in noncalcified coronary artery plaque volume ○ No CV events reported ○ Unclear clinical significance ○ Plaque formation? concern about testosterone use in older men

More on Cardiovascular Risks:

● Mixed opinions on testosterone effects

● Beneficial?

○ Rottenham Study-Lower testosterone associated with increased atherosclerosis

○ Carotid Artery Study

○ TRT-improved exercise tolerance

○ Improved HDL levels

○ ? Cardioprotective

● Detrimental?

○ VA study-retrospective. TRT increased risk for MI, Stroke

○ Flawed study. Controversial

Cardiovascular Risks:

Large, Long-term studies are needed to further evaluate the risks of testosterone replacement therapy and CV risks.

Prostate Cancer/BPH:

● Most epidemiologic studies have shown no association between testosterone levels and the incidence of prostate cancer

● Treatment may stimulate growth in previously undiagnosed prostate cancer

● No studies suggest testosterone replacement therapy as a cause of prostate cancer

● Prostate cancer is partially testosterone dependant. Low testosterone + prostate

cancer is a more virulent disease.

● Prostate enlargement was minimal. Small decrease in max flow rate

Summary:

● Testosterone replacement therapy is increasing

● The diagnosis requires a careful evaluation

● Treatment requires an established diagnosis and symptoms

● The benefits of testosterone therapy may be significant in patients with symptoms

● The benefits for age-related hypogonadism appear limited (sexual function, anemia,

bone health)

● The relationship between testosterone replacement therapy and CV disease remains

unclear.

Testosterone Replacement Therapy: Goals

● Improve libido, mood and general well-being ● Increase muscle mass ● Prevent bone loss

Testosterone Replacement Therapy: Contraindications

● Prostate/ Breast Cancer ● HCt >55% ● BPH ● Sleep Apnea ● CHF

Benefits: Risks:

● Increased muscle mass ● Sex drive ● Improved mood ● Vitality ● Cognition ● Bone density ● CV benefit?

● Erythrocytosis ● Gynecomastia ● Worsening OSA ● Infertility ● CV risks?

Testosterone Replacement Therapy: IM Injections

● Testosterone Cypionate (Depo-Testosterone) ○ ½ life 8 days ○ 200 mg every other week

● Testosterone Enanthate

○ ½ life 4.5 days ○ 100 mg every week

● Testosterone Undecantoate (Aveed)

○ 750 mg IM q 10 weeks (1000mg/12 weeks)

● Inexpensive

● Symptom fluctuation due to peaks and nadir

● Increased polycythemia

● MD visits for injection

● Can be taught to do this at

home with closer monitoring

Testosterone Replacement Therapy: Gels

● Androgel, Testim, Axiron

● Convenient

● Simple to use

● Very effective

● Most physiologic replacement

● Gels can transfer (partner/kids)

● Less skin irritation

Testosterone Replacement Therapy: Patches

● Limited by $$$ ● Skin irritation

Testosterone Replacement Therapy: Buccal Disc

● Striant ○ 30 mg buccal disc q 12 hours

● $$$

Testosterone Replacement Therapy: Oral

● Not used in US ● Europe 2-3x daily with food

Testosterone Replacement Therapy: Subcutaneous pellets

● Testopel

● 6-10 Pellets

● Last 3-9 months

● Expensive

● Clinical response slower

● Abused “Low-T” clinics

Testosterone Replacement Therapy: Goal

● Target should be a testosterone in the mid-normal range 400-700 ng/dL ○ Do not adjust based on symptoms ○ Adjust dose or frequency

● Hemoglobin ○ Check at baseline at at 3-6 months then every 6-12 months ○ Halt therapy if HCT >54% ○ Adjust dose or frequency after HCT returns to normal level

● PSA

○ Baseline ○ Repeat at 3-6 months then every 6-12 months based on risks

Thank you

jeremiah murphy, md mercy urology clinic testosterone may be a crucial factor in chronic disease...

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